Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus acids or salts thereof
Patent
1995-03-28
1996-08-06
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus acids or salts thereof
514107, 514108, 558158, C07F 938, A61K 3166
Patent
active
055435610
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns new amidine group-containing diphosphonic acid derivatives, processes for their preparation, as well as medicaments which contain these substances.
In DE 18 13 659 are described diphosphonic acid derivatives of which 1-hydroxyethane-1,1-diphosphonic acid has achieved importance as agent for the treatment of Paget's disease.
EP-A-282,320 describes substituted 3-isoxazolyl-aminomethylenediphosphonic acids and their esters with anti-hypercalcaemic and antiarthritic action.
In EP-A-282,309 there are described "azol"-aminomethylenediphosphonic acids as hypercalcaemic inhibitors.
Furthermore, from JP-A-63/150 290 one knows aminomethylenediphosphonic acids as regulators of the calcium metabolism and from EP-A-274,158 tetrahydropyrimidinyl- and tetrahydropyridylaminomethylenediphosphonic acids for the treatment of an abnormal calcium and phosphate metabolism.
One knows cyclic amidine group-containing geminal diphosphonic acids from DE-A-3 208 600, Liebigs Ann. Chem. 1982, 275 and DE-A-39 30 130.3.
It has now been found that acyclic derivatives of these compounds are extraordinarily good calcium complex formers but, in addition, also show an excellent action on the calcium metabolism and thus are suitable for the broad treatment of calcium metabolism disturbances. Above all, they can be very well used there where the bone build-up and breakdown is disturbed, i.e. they are suitable for the treatment of diseases of the skeletal system, such as e.g. osteoporosis, Paget's disease, Bechterew's disease and the like.
However, on the basis of these properties, they also find use in the therapy of bone metastases, of urolithiasis and for the prevention of heterotopic ossifications. Furthermore, by means of their influencing of the calcium metabolism, they form a basis for the treatment of rheumatoid arthritis, of osteoarthritis and of degenerative arthrosis.
Consequently, the subject of the present invention are diphosphonates of the general formula I ##STR2## in which R.sup.1 signifies hydrogen, a straight-chained, branched, saturated or unsaturated alkyl radical with 1-9 carbon atoms possibly substituted by phenyl or a phenyl ring which is possibly substituted by C.sub.1 -C.sub.3 -alkyl, C.sub.1 -C.sub.3 -alkoxy or halogen, R.sup.2 signifies hydrogen or C.sub.1 -C.sub.3 -alkyl, whereby the two radicals can be the same or different, R represents hydrogen or a straight-chained or branched alkyl radical with 1-4 carbon atoms, X signifies an alkylene chain with 1-6 carbon atoms which can be substituted one or more times by C.sub.1 -C.sub.3 -alkyl and can possibly be interrupted by oxygen, whereby 1 or 2 carbon atoms of the alkylene chain can possibly be part of a cyclopentyl or cyclohexyl ring and Y signifies hydrogen, hydroxyl or amino possibly substituted by alkyl groups with 1-6 carbon atoms, as well as their pharmacologically acceptable salts.
Y preferably stands for hydrogen, hydroxyl or amino group which can be substituted by methyl, ethyl or isopropyl.
For the group X, there preferably comes into question an ethylene, propylene, butylene, 1-methylpropylene, 2-methylpropylene, 1-methylbutylene or 2-methylbutylene radical.
Furthermore, X preferably represents a 1,1- or 1,2-substituted cyclohexyl or cyclopentyl ring which is connected to the biphosphonic acid part via methylene, ethylene or propylene.
R preferably signifies hydrogen or the methyl, ethyl or isobutyl radical.
Compounds are especially preferred in which R and R.sup.2 is hydrogen, Y signifies hydrogen or hydroxyl group and R.sup.1 represents hydrogen or an alkyl radical.
X stands especially preferably for methylene, ethylene, propylene or butylene radical.
The compounds can be present as stereoisomeric mixture or as pure cis or trans isomers.
Asymmetric carbon atoms can possess the R- or S- configuration and the compounds can be present optically-active or as racemates.
The compounds of gen. formula I are prepared according to per se known processes, preferably in that one reacts a carboxylic acid of the general formula II ##STR
REFERENCES:
patent: 4705651 (1987-11-01), Staibano
patent: 5281748 (1994-01-01), Jaeggi
patent: 5294608 (1994-03-01), Lang et al.
patent: 5366965 (1994-11-01), Strein
patent: 5366969 (1994-11-01), Bosies et al.
patent: 5395826 (1995-03-01), Naumann et al.
Bauss Frieder
Zilch Harald
Boehringer Mannheim GmbH
Frazier Barbara S.
Ivy C. Warren
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